Studies on axon regeneration and recovery in rodents have revealed that the spinal cord is not hard wired and ?learning? can occur in spinal cord circuits. Compounds that elicit axonal regeneration and sprouting help plasticity in the spinal cord and dramatically improve recovery from traumatic injury, at least in rodents. Intrinsic signals that progress with normal neuronal differentiation play a significant role in preventing axon regeneration. Several intrinsic negative regulators of regeneration have been identified through studies of knock-out mice. Suppression of synthesis of PTEN protein can promote axon regeneration and recovery of motor function in adult rodents. There has been a concerning lack of translation in SCI research for the most promising targets, and therefore we decided to create a compound with potential for therapeutic development. We chose the technology of self-deliverable RNA interference (sd-rxRNAi) because of the simplicity and proven efficacy of in vivo delivery to the central nervous system. BA- 434 as a novel sd-rxRNA that targets mRNA encoding PTEN and suppress the expression of PTEN protein. It has sequence homology to rat, pig and human, and was selected from 20 that we screened. We propose to further development of BA-434 and carry out IND-enabling safety and efficacy experiments to translate these findings to clinical study. We will optimize stability of BA-434, and dose and efficacy in spinal cord injury models. We will also confirm appropriate drug delivery in pig spinal cord because the size of pig spinal cord better approximates the size of human spinal cord. The proposed research will form the basis of non-GLP safety and efficacy studies in support of an IND application.